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BAY AREA CANCER TARGET DISCOVERY AND DEVELOPMENT NETWORK

Summary: The exploration of extracellular RNAs in mouse models is an important precept for the development of therapeutic intervention. Our study develops new technologies that promise to expedite identifying mechanisms for RNA based drug delivery.

Currently, enormous volumes of data are being generated by the comprehensive molecular characterization of a number of human tumors. The ability to effectively and efficiently use CRSPR to assess the biologic consequences of gene target inhibition is of critical importance to understanding gene function and to uncover tumor-specific vulnerabilities. The identification of tumor-specific vulnerabilities provides rationale for the development of biologically-based targeted therapies.

CRISPR screening is a powerful technology for high- throughput gene function discovery that has been used to identify tumor-specific vulnerabilities. We develop technologies and resources that overcome technical limitations, dramatically advancing screening capabilities. We take advantage of statistically-based analyses and the power of new deep sequencing technologies that have been rapidly democratized. Our new approaches will greatly facilitate the development of cancer polytherapies, opening a new paradigm for rationally-based cancer therapeutics that fully capitalize on genomic profiling of human tumors.

To design effective combination cancer therapies (polytherapies) we must first identify the signaling pathways that act synergistically to promote tumor growth or therapeutic resistance. This knowledge then enables the design of therapies that target these key cancer "driver" pathways. A major obstacle to the development of therapies that preclude or overcome resistance to targeted cancer therapy is that there is no systematic means by which to identify pathways that functionally cooperate and synergize to drive tumor growth or therapeutic resistance. Therefore, the search for effective cancer polytherapies has been done largely in an ad hoc manner exploring only a very limited number of potential combinations.

The key to rationally designing an optimal combination of therapies lies in the systematic identification of pathways that when targeted, lead to specific and synergistic destruction of cancer cells. Our new approaches can determine simultaneously and rapidly (within 1-3 weeks) high precision measures of functional genetic interactions between large numbers (typically hundreds of thousands to hundreds of million pairs) of sgRNAs that target genes of interest in the context of any cancer. This represents a transformative technology in terms of our ability to systematically uncover cancer- relevant gene interaction networks that drive tumor growth and that potentially can be exploited as rational, tumor-specific polytherapies.